DNA nanomachine strategy reverses chemoresistance in small cell lung cancer

Professor Chao Zhang's team at Zhujiang Hospital, Southern Medical University, has developed a novel DNA nanomachine-based drug delivery and release strategy aimed at overcoming chemoresistance in small cell lung cancer (SCLC). The team identified the PRMT1/SOX2 signaling axis as a key driver of chemotherapy resistance in SCLC and, based on this mechanism, designed a DNA nanomachine capable of temporally programmed drug release. By precisely targeting chemoresistant tumor cells, the nanomachine rapidly releases a stemness inhibitor followed by the sustained release of the chemotherapeutic agent cisplatin, thereby effectively reversing tumor stemness and significantly enhancing chemosensitivity.

Research background

Chemoresistance remains one of the primary causes of treatment failure in cancer therapy and is often associated with increased tumor invasion, metastasis, and poor prognosis. Beyond limited drug delivery efficiency, chemoresistance is strongly influenced by intrinsic cellular signaling networks that regulate multiple biological characteristics. Among these, tumor stemness - defined by the capacity for self-renewal and differentiation - has been widely recognized as a central driver of chemoresistance and tumor recurrence. However, the molecular mechanisms governing stemness and effective strategies to target it remain incompletely understood.

Research progress

Professor Zhang's team systematically elucidated the critical role of PRMT1 in SCLC. Their findings showed that PRMT1 is markedly upregulated in chemoresistant SCLC cells and closely correlated with poor patient prognosis. Mechanistic studies revealed that PRMT1 promotes chemoresistance by activating SOX2-mediated tumor stemness. Inhibition of PRMT1 significantly reduced stemness and enhanced sensitivity to cisplatin, establishing the PRMT1-SOX2 axis as a key resistance-driving pathway and a promising therapeutic target.

Building on these insights, the researchers constructed a DNA nanomachine-based delivery system that simultaneously loads the PRMT1 inhibitor DCLX069 and cisplatin. This system enables a programmed therapeutic sequence within tumor cells: rapid release of DCLX069 to suppress tumor stemness, followed by the gradual release of cisplatin to maximize cytotoxic efficacy. The DNA nanomachine demonstrated excellent tumor-targeting capability both in vitro and in vivo.

In cellular and animal models, this nanotherapeutic system effectively reversed chemoresistance in SCLC and significantly inhibited tumor growth. Compared with conventional intravenous cisplatin administration, the DNA nanomachine markedly reduced cisplatin-associated hematological and renal toxicity and did not induce obvious immunogenic responses, highlighting its favorable biosafety profile and strong potential for clinical translation.

Future perspectives

Owing to the high programmability of DNA-based materials, this nanotherapeutic strategy may be extended to other chemoresistant tumor types and adapted for multi-target and personalized precision therapies. With further optimization of structural design, dosing regimens, and scalable manufacturing processes, this DNA nanomachine platform holds promise for advancing chemosensitization strategies toward clinical application and offers a novel solution for overcoming tumor chemoresistance.